RESUMO
Metabolic syndrome (MS) is comprised of a cluster of abnormalities in glucose, lipid, and vascular homeostasis, which is most commonly linked to abdominal obesity. MS heralds increased risk for development of diabetes and is linked to impairment in insulin signaling. Insulin-degrading enzyme (IDE) is one of the mechanisms through which insulin blood levels are maintained. It has been previously suggested that controlling IDE levels could provide yet another potential therapeutic approach in diabetes. Here we aim to investigate whether changes in serum IDE levels correlate with the severity of MS. Using a highly sensitive ELISA assay of active IDE in human serum, we found a strong correlation between circulating IDE levels and circulating levels of triglycerides, insulin, and c-peptide and an inverse correlation with HDL cholesterol (HDLc). Serum IDE levels were higher in MS subjects than in control subjects. Hence, circulating IDE may serve as a tool to identify subjects with abnormal insulin metabolism, possibly those with MS that are at risk to develop diabetes.
Assuntos
Insulisina , Síndrome Metabólica , Peptídeo C , Teste de Tolerância a Glucose , Humanos , InsulinaRESUMO
LAP2beta is an integral membrane protein of the nuclear envelope involved in chromatin and nuclear architecture. Using the yeast two-hybrid system, we have cloned a novel LAP2beta-binding protein, mGCL, which contains a BTB/POZ domain and is the mouse homologue of the Drosophila germ-cell-less (GCL) protein. In Drosophila embryos, GCL was shown to be essential for germ cell formation and was localized to the nuclear envelope. Here, we show that, in mammalian cells, GCL is co-localized with LAP2beta to the nuclear envelope. Nuclear fractionation studies reveal that mGCL acts as a nuclear matrix component and not as an integral protein of the nuclear envelope. Recently, mGCL was found to interact with the DP3alpha component of the E2F transcription factor. This interaction reduced the transcriptional activity of the E2F-DP heterodimer, probably by anchoring the complex to the nuclear envelope. We demonstrate here that LAP2beta is also capable of reducing the transcriptional activity of the E2F-DP complex and that it is more potent than mGCL in doing so. Co-expression of both LAP2beta and mGCL with the E2F-DP complex resulted in a reduced transcriptional activity equal to that exerted by the pRb protein.
Assuntos
Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila , Proteínas de Membrana/metabolismo , Membrana Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Transporte/fisiologia , Cromossomos/química , Proteínas de Ligação a DNA/química , Drosophila , Fatores de Transcrição E2F , Humanos , Insulinoma/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Neoplasias Pulmonares , Substâncias Macromoleculares , Proteínas de Membrana/química , Camundongos , Dados de Sequência Molecular , Membrana Nuclear/química , Proteínas Nucleares/genética , Proteínas Nucleares/isolamento & purificação , Pâncreas/citologia , Pâncreas/metabolismo , Transporte Proteico/fisiologia , Saccharomyces cerevisiae , Homologia de Sequência , Transcrição Gênica/fisiologia , Células Tumorais Cultivadas/metabolismoRESUMO
BACKGROUND: Promising results have been reported for patients with non-Hodgkin's lymphoma (NHL) receiving chronic oral etoposide. Due to the small number of patients reported, information regarding side effects is limited, and therefore warrants further evaluation. METHODS: Twenty eligible patients with NHL and chronic lymphatic leukemia (CLL), resistant to or relapsed after previous protocols of polychemotherapy were treated with oral etoposide at a dosage of 50 mg/m2/day for 21 days in a 28-day cycle. Response and toxicity were evaluated according to standard criteria. RESULTS: Total response was noted in 13 patients, complete response in 2 patients, and partial response in 11 patients. Two patients had stable disease and five patients had progression of disease during treatment. Seventy-five percent of patients experienced neutropenia below 1500/microL. Half acquired infection and required hospitalization. Fifty-five percent required blood transfusions. All patients needed course shortening and dosage reduction. CONCLUSIONS: Chronic daily administration of oral etoposide is effective in patients with NHL and CLL. In heavily pretreated patients, myelotoxicity is severe. Therefore, modification of the schedule plan is mandatory in this group of patients.